Immune function declines with age. In order to extend quality of life, it is critical that we understand mechanisms underlying the age-associated decline in immune function. Humans are riddled throughout life with a variety of acute and chronic infections which trigger the immune system. The accumulating effect of acute and chronic infections throughout the lifespan profoundly impacts the T cell repertoire and immune response of aged individuals. Although the aging mouse model provides a robust experimental model amenable to addressing mechanisms, it is increasingly realized that an important limitation of the mouse model is that mice are typically housed in specific pathogen free conditions. Immune senescence cannot be appropriately modeled in mice in which antigen experience has been deliberately constrained. In addition, optimal immune responses to new infections are thought to be dependent on a diverse repertoire of nave T cells. With age, the numbers and diversity of nave T cells decline and the ratio of memory to nave T cells greatly increases. It has been determined that T cell recognition of antigen/MHC is highly degenerate and T cell responses exhibit extensive and unexpected cross reactivity. We hypothesize that, with the declining numbers of nave T cells with age, the response to new infections become increasingly dependent on memory cells that accumulated with antigen experience and are fortuitously cross reactive. The first goal of this proposal is to develop a better mouse model for aging by defined exposure early in life to sequential infection with chronic and acute viruses. The second goal of this developmental R21 is to test the hypothesis that sequentially-infected aged mice, by virtue of enhanced antigen experience, will manifest increased diversity in the memory T cell repertoire capable of cross- reacting with new infections. Accomplishing the goals of this developmental R21 will be an important advance for aging research. Studies in antigen-experienced aged mice will benefit understanding the impact of antigen experience on immunity and senescence in elderly humans and has important implications for vaccination strategies for the elderly, supporting the concept that vaccines in young and middle age are important for maintaining immunity in later life.